Project Summary Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States. Recent North American practice guidelines recommend semi-annual HCC surveillance using ultrasound (US) with or without serum alpha-fetoprotein (AFP) for cirrhotic and other high-risk patients to permit detection of HCC at an early stage, enabling effective treatment, and potentially improving survival. However, US suffers from limited performance in patients with cirrhosis and overweight/obesity, causing the sensitivity of US for early-stage HCC to be as low as 40%. We recently conceived and tested a novel abbreviated magnetic resonance imaging (AMRI) exam including T1-weighted imaging (T1-w) at the hepatobiliary phase post gadoxetic acid injection (HBP-AMRI) designed to detect HCC in cirrhotic patients with improved accuracy, with only 2 sequences (T1-w HBP at 20 min post injection and T2-w). Our preliminary data suggest that HBP-AMRI provides >80% sensitivity for HCC detection. Here, we propose a prospective multicenter (composed of the Icahn School of Medicine at Mount Sinai, University of California, San Diego, University of Wisconsin-Madison and Duke University) study to assess the performance of HBP-AMRI as a screening modality for early detection of HCC in 820 Americans with cirrhosis. A complete MRI (which includes dynamic imaging, HBP imaging, and other sequences) will be disaggregated to reconstruct an HBP-AMRI exam. Using this reconstructed exam, we will test our central hypothesis that HBP-AMRI is more sensitive and cost-effective than US for HCC detection. We will also assess the incremental diagnostic value of circulating tumor DNA (ctDNA) and serum AFP. Specifically, we aim to determine the: 1) diagnostic performance of HBP-AMRI vs. US for HCC screening in cirrhotic patients. 2) added value of ctDNA and serum AFP for improving HCC detection by HBP- AMRI or US in cirrhotic patients, 3) cost-effectiveness of HBP-AMRI versus US for HCC screening in cirrhotic patients. Finally, we will reconstruct a gadoxetic acid-enhanced (Dyn-AMRI) exam from the complete exam for exploratory analyses of the diagnostic performance of Dyn-AMRI vs HBP-AMRI and US for HCC screening. Our long-term objective is to validate an accurate and precise method for improving the screening and surveillance for HCC in patients with cirrhosis, with potential mortality reduction from HCC. The successful completion of this proposal will help validate a novel screening method comprising HBP-AMRI, possibly combined with ctDNA.